Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation, which includes a switch from an articular to a growth-plate chondrocyte phenotype. Epigenetics serves as a new therapeutic target but histone modification changes in OA remain elusive. Here, we investigated the profiles of four histone modifications in normal and OA chondrocytes. The repressive mark H3K27me3 was significantly lost in OA, associated with up-regulated gene expression. Surprisingly, many of these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. These bivalent genes are deemed to be activated during the hypertrophy of growth plate chondrocytes. Furthermore, inflammation induced the expression of demethylase KDM6B and decreased H3K27me3 level in OA chondrocytes, which was rescued by the KDM6B inhibitor GSK-J4. Altogether, our results suggest an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contribute to a promising epigenetic therapy for OA.

The authors have declared no competing interest.

This work was supported by National Natural Science Foundation of China (81874027, U22A20280); Science & Technology Department of Sichuan Province (2023NSFSC1607?2021YFSY0003?2022YFS0051?2022NSFSC1312); Shenzhen-HongKong Institute of Brain Science-Shenzhen Fundamental Research Institutions (312200102); Clinical Research Incubation project of West China Hospital of Sichuan University (2021HXFH036).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Committee on Biomedical Research, West China Hospital of Sichuan University Institutional Animal Care and Use Committee (IACUC) of the Sichuan University

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The CUT&Tag and RNA-seq data generated in this study have been deposited in the NCBI's Sequence Read Archive (SRA) database under accession code PRJNA930583. The mouse PC and HC ChIP-seq data was downloaded through the GEO accession numbers. All code required for data analyses and figure preparation are available at https://github.com/luciferase1234/Inflammation-induced-epigenetic-activation-of-bivalent-genes-in-osteoarthritic-cartilage. All data are available in the main text or the supplementary materials.

https://github.com/luciferase1234/Inflammation-induced-epigenetic-activation-of-bivalent-genes-in-osteoarthritic-cartilage